The endothelium plays a critical role in the maintenance of cardiovascular health by producing nitric oxide and other vasoactive materials. Aging is associated with a gradual decline in this functional aspect of endothelial regulation of cardiovascular homeostasis. Indeed, age is an independent risk factor for cardiovascular diseases and is in part an important factor in the increased exponential mortality rates from vascular disease such as myocardial infarction and stroke that occurs in the ageing population. There are a number of mechanisms suggested to explain age-related endothelial dysfunction. However, recent scientific studies have advanced the notion of oxidative stress and inflammation as the two major risk factors underlying aging and age-related diseases. Regular physical activity, known to have a favorable effect on cardiovascular health, can also improve the function of the ageing endothelium by modulating oxidative stress and inflammatory processes, as we discuss in this paper. 1. Introduction The global population, especially those in developed countries, is getting older and this trend is predicted to continue in the coming decades [1, 2]. Some have defined aging as a decreased ability to resist cellular stresses or insults [3, 4], and in fact, aging is one of the most important cardiovascular risk factors for predisposing conditions such as diabetes, hypertension, and hypercholesterolemia. Accordingly, the incidence and prevalence of clinical and subclinical cardiovascular diseases increase dramatically with age [2], making cardiovascular disease the most common cause of death among the elderly. The endothelium has a primary role in adjusting vascular function by the production of nitric oxide (NO) and other biologically active vasodilator materials [5] that decrease vascular resistance, inhibit platelet adhesion and aggregation, and decrease vascular smooth muscle cell proliferation. Alterations in the control of these processes, a feature of endothelial dysfunction, often leads to atherosclerosis and other vascular disorders [6] that are accompanied by a proinflammatory, proliferative, and procoagulatory state [7]. The endothelium is ideally placed to bear the brunt of hemodynamic stresses, oxidized lipids, and oxidative radicals, all of which increase their vulnerability to aging [8]. Chronic aerobic exercise improves cardiovascular function in humans. This is true not only in healthy subjects without underlying risk factors [9], but also in older people [10] and those with cardiovascular risk factors [11]. Indeed, those with
References
[1]
S. Yusuf, S. Reddy, S. ？unpuu, and S. Anand, “Global burden of cardiovascular diseases—part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization,” Circulation, vol. 104, no. 22, pp. 2746–2753, 2001.
[2]
National Centre for Health Statistics (US), http://www.cdc.gov./nchs/hus.htm.
[3]
B. P. Yu, “Aging and oxidative stress: modulation by dietary restriction,” Free Radical Biology and Medicine, vol. 21, no. 5, pp. 651–668, 1996.
[4]
K. B. Beckman and B. N. Ames, “The free radical theory of aging matures,” Physiological Reviews, vol. 78, no. 2, pp. 547–581, 1998.
[5]
J. A. Vita, “Nitric oxide-dependent vasodilation in human subjects,” Methods in Enzymology, vol. 359, pp. 186–200, 2002.
[6]
P. O. Bonetti, L. O. Lerman, and A. Lerman, “Endothelial dysfunction: a marker of atherosclerotic risk,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 2, pp. 168–175, 2003.
[7]
T. J. Anderson, “Assessment and treatment of endothelial dysfunction in humans,” Journal of the American College of Cardiology, vol. 34, no. 3, pp. 631–638, 1999.
[8]
H. Y. Chung, H. J. Kim, J. W. Kim, and B. P. Yu, “The inflammation hypothesis of aging: molecular modulation by calorie restriction,” Annals of the New York Academy of Sciences, vol. 928, pp. 327–335, 2001.
[9]
P. Clarkson, H. E. Montgomery, M. J. Mullen et al., “Exercise training enhances endothelial function in young men,” Journal of the American College of Cardiology, vol. 33, no. 5, pp. 1379–1385, 1999.
[10]
E. J. Benjamin, M. G. Larson, M. J. Keyes et al., “Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study,” Circulation, vol. 109, no. 5, pp. 613–619, 2004.
[11]
R. Hambrecht, E. Fiehn, C. Weigl et al., “Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure,” Circulation, vol. 98, no. 24, pp. 2709–2715, 1998.
[12]
A. Maiorana, G. O'Driscoll, C. Cheetham et al., “The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes,” Journal of the American College of Cardiology, vol. 38, no. 3, pp. 860–866, 2001.
[13]
A. Maiorana, G. O'Driscoll, L. Dembo, C. Goodman, R. Taylor, and D. Green, “Exercise training, vascular function, and functional capacity in middle-aged subjects,” Medicine and Science in Sports and Exercise, vol. 33, no. 12, pp. 2022–2028, 2001.
[14]
S. Verma and T. J. Anderson, “Fundamentals of endothelial function for the clinical cardiologist,” Circulation, vol. 105, no. 5, pp. 546–549, 2002.
[15]
F. Cosentino and E. Osto, “Aging and endothelial dysfunction,” Clinical Hemorheology and Microcirculation, vol. 37, pp. 143–147, 2007.
[16]
J. Deanfield, A. Donald, C. Ferri et al., “Endothelial function and dysfunction—part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension,” Journal of Hypertension, vol. 23, no. 1, pp. 7–17, 2005.
[17]
S. Golbidi, A. Mesdaghinia, and I. Laher, “Exercise in the metabolic syndrome,” Oxidative Medicine and Cellular Longevity, vol. 2012, Article ID 349710, 13 pages, 2012.
[18]
J. B. Michel, O. Feron, D. Sacks, and T. Michel, “Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin,” Journal of Biological Chemistry, vol. 272, no. 25, pp. 15583–15586, 1997.
[19]
C. Dessy, O. Feron, and J.-L. Balligand, “The regulation of endothelial nitric oxide synthase by caveolin: a paradigm validated in vivo and shared by the ‘endothelium-derived hyperpolarizing factor’,” Pflugers Archiv—European Journal of Physiology, vol. 459, no. 6, pp. 817–827, 2010.
[20]
F. Bobeuf, M. Labonte, I. J. Dionne, and A. Khalil, “Combined effect of antioxidant supplementation and resistance training on oxidative stress markers, muscle and body composition in an elderly population,” Journal of Nutrition, Health and Aging, vol. 15, no. 10, pp. 883–889, 2011.
[21]
S. D. Anton, T. M. Manini, V. A. Milsom et al., “Effects of a weight loss plus exercise program on physical function in overweight, older women: a randomized controlled trial,” Clinical Interventions in Aging, vol. 6, no. 1, pp. 141–149, 2011.
[22]
L. B. Gano, A. J. Donato, G. L. Pierce et al., “Increased proinflammatory and oxidant gene expression in circulating mononuclear cells in older adults: amelioration by habitual exercise,” Physiological Genomics, vol. 43, no. 14, pp. 895–902, 2011.
[23]
P. T. Campbell, M. D. Gross, J. D. Potter et al., “Effect of exercise on oxidative stress: a 12-month randomized, controlled trial,” Medicine and Science in Sports and Exercise, vol. 42, no. 8, pp. 1448–1453, 2010.
[24]
D. W. Wray, A. Uberoi, L. Lawrenson, D. M. Bailey, and R. S. Richardson, “Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome,” Clinical Science, vol. 116, no. 5, pp. 433–441, 2009.
[25]
S. Sixt, A. Rastan, S. Desch et al., “Exercise training but not rosiglitazone improves endothelial function in prediabetic patients with coronary disease,” European Journal of Cardiovascular Prevention and Rehabilitation, vol. 15, no. 4, pp. 473–478, 2008.
[26]
J. U. Gonzales, J. R. Thistlethwaite, B. C. Thompson, and B. W. Scheuermann, “Exercise-induced shear stress is associated with changes in plasma von Willebrand factor in older humans,” European Journal of Applied Physiology, vol. 106, no. 5, pp. 779–784, 2009.
[27]
W.-H. Xia, J. Li, C. Su et al., “Physical exercise attenuates age-associated reduction in endothelium-reparative capacity of endothelial progenitor cells by increasing CXCR4/JAK-2 signaling in healthy men,” Aging Cell, vol. 11, no. 1, pp. 111–119, 2012.
[28]
G. L. Pierce, I. Eskurza, A. E. Walker, T. N. Fay, and D. R. Seals, “Sex-specific effects of habitual aerobic exercise on brachial artery flow-mediated dilation in middle-aged and older adults,” Clinical Science, vol. 120, no. 1, pp. 13–23, 2011.
[29]
G. P. van Guilder, C. M. Westby, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza, “Endothelin-1 vasoconstrictor tone increases with age in healthy men but can be reduced by regular aerobic exercise,” Hypertension, vol. 50, no. 2, pp. 403–409, 2007.
[30]
C. A. da Silva, J. P. Ribeiro, J. C. A. U. Canto et al., “High-intensity aerobic training improves endothelium-dependent vasodilation in patients with metabolic syndrome and type 2 diabetes mellitus,” Diabetes Research and Clinical Practice, vol. 95, no. 2, pp. 237–245, 2012.
[31]
S. Okada, A. Hiuge, H. Makino et al., “Effect of exercise intervention on endothelial function and incidence of cardiovascular disease in patients with type 2 diabetes,” Journal of Atherosclerosis and Thrombosis, vol. 17, no. 8, pp. 828–833, 2010.
[32]
M. Vona, G. M. Codeluppi, T. Iannino, E. Ferrari, J. Bogousslavsky, and L. K. von Segesser, “Effects of different types of exercise training followed by detraining on endothelium-dependent dilation in patients with recent myocardial infarction,” Circulation, vol. 119, no. 12, pp. 1601–1608, 2009.
[33]
K. Yamamoto and J. Ando, “New molecular mechanisms for cardiovascular disease: blood flow sensing mechanism in vascular endothelial cells,” Journal of Pharmacological Sciences, vol. 116, no. 4, pp. 323–331, 2011.
[34]
S. Gielen, G. Schuler, and V. Adams, “Cardiovascular effects of exercise training: molecular mechanisms,” Circulation, vol. 122, no. 12, pp. 1221–1238, 2010.
[35]
C. A. Stuart, R. E. Shangraw, M. J. Prince, E. J. Peters, and R. R. Wolfe, “Bed-rest-induced insulin resistance occurs primarily in muscle,” Metabolism, vol. 37, no. 8, pp. 802–806, 1988.
[36]
P. J. Arciero, D. L. Smith, and J. Calles-Escandon, “Effects of short-term inactivity on glucose tolerance, energy expenditure, and blood flow in trained subjects,” Journal of Applied Physiology, vol. 84, no. 4, pp. 1365–1373, 1998.
[37]
J. Smorawiński, H. Kaciuba-U？ci？ko, K. Nazar et al., “Effects of three-day bed rest on metabolic, hormonal and circulatory responses to an oral glucose load in endurance or strength trained athletes and untrained subjects,” Journal of Physiology and Pharmacology, vol. 51, no. 2, pp. 279–289, 2000.
[38]
S. S. Thosar, B. D. Johnson, J. D. Johnston, and J. P. Wallace, “Sitting and endothelial dysfunction: the role of shear stress,” Medical Science Monitor, vol. 18, pp. RA173–RA180, 2012.
[39]
C. Demiot, F. Dignat-George, J.-O. Fortrat et al., “WISE 2005: chronic bed rest impairs microcirculatory endothelium in women,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 293, no. 5, pp. H3159–H3164, 2007.
[40]
S. di Francescomarino, A. Sciartilli, V. di Valerio, A. di Baldassarre, and S. Gallina, “The effect of physical exercise on endothelial function,” Sports Medicine, vol. 39, no. 10, pp. 797–812, 2009.
[41]
T. F. Luscher and G. Noll, “The endothelium in coronary vascular control,” Heart Disease, vol. 3, pp. 1–10, 1995.
[42]
P. W. Vanhoutte, “Ageing and endothelial dysfunction,” European Heart Journal, vol. 4, pp. A8–A17, 2002.
[43]
E. G. Lakatta, “Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises—part III: cellular and molecular clues to heart and arterial aging,” Circulation, vol. 107, no. 3, pp. 490–497, 2003.
[44]
R. P. Brandes, I. Fleming, and R. Busse, “Endothelial aging,” Cardiovascular Research, vol. 66, no. 2, pp. 286–294, 2005.
[45]
K. Rahman, “Studies on free radicals, antioxidants, and co-factors,” Clinical Interventions in Aging, vol. 2, no. 2, pp. 219–236, 2007.
[46]
H. Cai and D. G. Harrison, “Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress,” Circulation Research, vol. 87, no. 10, pp. 840–844, 2000.
[47]
S. Taddei, A. Virdis, L. Ghiadoni et al., “Age-related reduction of NO availability and oxidative stress in humans,” Hypertension, vol. 38, no. 2, pp. 274–279, 2001.
[48]
D. Sun, A. Huang, E. H. Yan et al., “Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 286, no. 6, pp. H2249–H2256, 2004.
[49]
T. Minamino, H. Miyauchi, T. Yoshida, Y. Ishida, H. Yoshida, and I. Komuro, “Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction,” Circulation, vol. 105, no. 13, pp. 1541–1544, 2002.
[50]
J. R. Durrant, D. R. Seals, M. L. Connell et al., “Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase,” Journal of Physiology, vol. 587, no. 13, pp. 3271–3285, 2009.
[51]
B. van der Loo, R. Labugger, J. N. Skepper et al., “Enhanced peroxynitrite formation is associated with vascular aging,” Journal of Experimental Medicine, vol. 192, no. 12, pp. 1731–1743, 2000.
[52]
M. R. Cernadas, L. Sánchez de Miguel, M. García-Durán et al., “Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats,” Circulation Research, vol. 83, no. 3, pp. 279–286, 1998.
[53]
S. Pennathur and J. W. Heinecke, “Oxidative stress and endothelial dysfunction in vascular disease,” Current Diabetes Reports, vol. 7, no. 4, pp. 257–264, 2007.
[54]
D. Versari, E. Daghini, A. Virdis, L. Ghiadoni, and S. Taddei, “The ageing endothelium, cardiovascular risk and disease in man,” Experimental Physiology, vol. 94, no. 3, pp. 317–321, 2009.
[55]
C. A. Hamilton, M. J. Brosnan, M. McIntyre, D. Graham, and A. F. Dominiczak, “Superoxide excess in hypertension and aging a common cause of endothelial dysfunction,” Hypertension, vol. 37, no. 2, pp. 529–534, 2001.
[56]
A. G？rlach, R. P. Brandes, K. Nguyen, M. Amidi, F. Dehghani, and R. Busse, “A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall,” Circulation Research, vol. 87, no. 1, pp. 26–32, 2000.
[57]
O. Jung, J. G. Schreiber, H. Geiger, T. Pedrazzini, R. Busse, and R. P. Brandes, “gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension,” Circulation, vol. 109, no. 14, pp. 1795–1801, 2004.
[58]
A. J. Donato, I. Eskurza, A. E. Silver et al., “Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-κB,” Circulation Research, vol. 100, no. 11, pp. 1659–1666, 2007.
[59]
I. V. Turko, S. Marcondes, and F. Murad, “Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 281, no. 6, pp. H2289–H2294, 2001.
[60]
Y. Liu and D. D. Gutterman, “The coronary circulation in diabetes: influence of reactive oxygen species on K+ channel-mediated vasodilation,” Vascular Pharmacology, vol. 38, no. 1, pp. 43–49, 2002.
[61]
Y. Liu, K. Terata, Q. Chai, H. Li, L. H. Kleinman, and D. D. Gutterman, “Peroxynitrite inhibits Ca2+-activated K+ channel activity in smooth muscle of human coronary arterioles,” Circulation Research, vol. 91, no. 11, pp. 1070–1076, 2002.
[62]
F. Soriano, L. Virág, and C. Szabó, “Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly(ADP-ribose) polymerase activation,” Journal of Molecular Medicine, vol. 79, no. 8, pp. 437–448, 2001.
[63]
I. Eskurza, L. A. Myerburgh, Z. D. Kahn, and D. R. Seals, “Tetrahydrobiopterin augments endothelium-dependent dilatation in sedentary but not in habitually exercising older adults,” Journal of Physiology, vol. 568, no. 3, pp. 1057–1065, 2005.
[64]
S. Lee, Y. Park, M. Y. Zuidema, M. Hannink, and C. Zhang, “Effects of interventions on oxidative stress and inflammation of cardiovascular diseases,” World Journal of Cardiology, vol. 3, pp. 18–24, 2011.
[65]
M. Barton, F. Cosentino, R. P. Brandes, P. Moreau, S. Shaw, and T. F. Lüscher, “Anatomic heterogeneity of vascular aging: role of nitric oxide and endothelin,” Hypertension, vol. 30, no. 4, pp. 817–824, 1997.
[66]
T. He, M. J. Joyner, and Z. S. Katusic, “Aging decreases expression and activity of glutathione peroxidase-1 in human endothelial progenitor cells,” Microvascular Research, vol. 78, no. 3, pp. 447–452, 2009.
[67]
F. P. Leung, L. M. Yung, I. Laher, X. Yao, Z. Y. Chen, and Y. Huang, “Exercise, vascular wall and cardiovascular diseases: an update (part 1),” Sports Medicine, vol. 38, no. 12, pp. 1009–1024, 2008.
[68]
S. Balducci, S. Zanuso, A. Nicolucci et al., “Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 20, no. 8, pp. 608–617, 2010.
[69]
A. H. Sprague and R. A. Khalil, “Inflammatory cytokines in vascular dysfunction and vascular disease,” Biochemical Pharmacology, vol. 78, no. 6, pp. 539–552, 2009.
[70]
S. Tiwari, Y. Zhang, J. Heller, D. R. Abernethy, and N. M. Soldatov, “Artherosclerosis-related molecular alteration of the human Ca V1.2 calcium channel α1C subunit,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 45, pp. 17024–17029, 2006.
[71]
J. Hiroki, H. Shimokawa, M. Higashi et al., “Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells,” Journal of Molecular and Cellular Cardiology, vol. 37, no. 2, pp. 537–546, 2004.
[72]
C. Zhang, Y. Park, A. Picchi, and B. J. Potter, “Maturation-induces endothelial dysfunction via vascular inflammation in diabetic mice,” Basic Research in Cardiology, vol. 103, no. 5, pp. 407–416, 2008.
[73]
J. A. Mitchell, S. Larkin, and T. J. Williams, “Cyclooxygenase-2: regulation and relevance in inflammation,” Biochemical Pharmacology, vol. 50, no. 10, pp. 1535–1542, 1995.
[74]
N. Erdei, Z. Bagi, I. édes, G. Kaley, and A. Koller, “H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in type 2 diabetic mice,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 292, no. 1, pp. H649–H656, 2007.
[75]
T. Matsumoto, M. Kakami, E. Noguchi, T. Kobayashi, and K. Kamata, “Imbalance between endothelium-derived relaxing and contracting factors in mesenteric arteries from aged OLETF rats, a model of type 2 diabetes,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 293, no. 3, pp. H1480–H1490, 2007.
[76]
E. H. C. Tang, F. P. Leung, Y. Huang et al., “Calcium and reactive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor,” British Journal of Pharmacology, vol. 151, no. 1, pp. 15–23, 2007.
[77]
H. J. Kim, K. J. Jung, B. P. Yu, C. G. Cho, J. S. Choi, and H. Y. Chung, “Modulation of redox-sensitive transcription factors by calorie restriction during aging,” Mechanisms of Ageing and Development, vol. 123, no. 12, pp. 1589–1595, 2002.
[78]
H. Y. Chung, B. Sung, K. J. Jung, Y. Zou, and B. P. Yu, “The molecular inflammatory process in aging,” Antioxidants and Redox Signaling, vol. 8, no. 3-4, pp. 572–581, 2006.
[79]
A. S. Baldwin Jr., “The NF-kappa B and I kappa B proteins: new discoveries and insights,” The Annual Review of Immunology, vol. 14, pp. 649–683, 1996.
[80]
P. J. Barnes and M. Karin, “Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases,” The New England Journal of Medicine, vol. 336, no. 15, pp. 1066–1071, 1997.
[81]
S. Ghosh, M. J. May, and E. B. Kopp, “NF-κB and rel proteins: evolutionarily conserved mediators of immune responses,” Annual Review of Immunology, vol. 16, pp. 225–260, 1998.
[82]
H. J. Kim, K. W. Kim, B. P. Yu, and H. Y. Chung, “The effect of age on cyclooxygenase-2 gene expression: NF-kappaB activation and IkappaBalpha degradation,” Free Radical Biology and Medicine, vol. 28, pp. 683–692, 2000.
[83]
H. Y. Chung, M. Cesari, S. Anton et al., “Molecular inflammation: underpinnings of aging and age-related diseases,” Ageing Research Reviews, vol. 8, no. 1, pp. 18–30, 2009.
[84]
S. B. Kritchevsky, M. Cesari, and M. Pahor, “Inflammatory markers and cardiovascular health in older adults,” Cardiovascular Research, vol. 66, no. 2, pp. 265–275, 2005.
[85]
A. Cartier, M. C？té, I. Lemieux et al., “Age-related differences in inflammatory markers in men: contribution of visceral adiposity,” Metabolism, vol. 58, no. 10, pp. 1452–1458, 2009.
[86]
H. Bruunsgaard, K. Andersen-Ranberg, B. Jeune, A. N. Pedersen, P. Skinh？j, and B. K. Pedersen, “A high plasma concentration of TNF-alpha is associated with dementia in centenarians,” The Journal of Gerontology: Series A, vol. 54, no. 7, pp. M357–M364, 1999.
[87]
A. A. Willette, B. B. Bendlin, D. G. McLaren et al., “Age-related changes in neural volume and microstructure associated with interleukin-6 are ameliorated by a calorie-restricted diet in old rhesus monkeys,” NeuroImage, vol. 51, no. 3, pp. 987–994, 2010.
[88]
B. Devaux, D. Scholz, A. Hirche, W. P. Klovekorn, and J. Schaper, “Upregulation of cell adhesion molecules and the presence of low grade inflammation in human chronic heart failure,” European Heart Journal, vol. 18, no. 3, pp. 470–479, 1997.
[89]
M. Maggio, J. M. Guralnik, D. L. Longo, and L. Ferrucci, “Interleukin-6 in aging and chronic disease: a magnificent pathway,” Journals of Gerontology: Series A, vol. 61, no. 6, pp. 575–584, 2006.
[90]
S. G. Wannamethee, A. G. Shaper, and P. H. Whincup, “Modifiable lifestyle factors and the metabolic syndrome in older men: effects of lifestyle changes,” Journal of the American Geriatrics Society, vol. 54, no. 12, pp. 1909–1914, 2006.
[91]
A. H. Mokdad, J. S. Marks, D. F. Stroup, and J. L. Gerberding, “Actual causes of death in the United States, 2000,” Journal of the American Medical Association, vol. 291, no. 10, pp. 1238–1245, 2004.
[92]
S. Golbidi and I. Laher, “Molecular mechanisms in exercise-induced cardioprotection,” Cardiology Research and Practice, vol. 2011, Article ID 972807, 15 pages, 2011.
[93]
S. Ghosh, S. Golbidi, I. Werner, B. C. Verchere, and I. Laher, “Selecting exercise regimens and strains to modify obesity and diabetes in rodents: an overview,” Clinical Science, vol. 119, no. 2, pp. 57–74, 2010.
[94]
C. A. Macera, J. M. Hootman, and J. E. Sniezek, “Major public health benefits of physical activity,” Arthritis Care and Research, vol. 49, no. 1, pp. 122–128, 2003.
[95]
C. A. Macera and K. E. Powell, “Population attributable risk: implications of physical activity dose,” Medicine and Science in Sports and Exercise, vol. 33, no. 6, pp. S635–S639, 2001.
[96]
J. Myers, A. Kaykha, S. George et al., “Fitness versus physical activity patterns in predicting mortality in men,” American Journal of Medicine, vol. 117, no. 12, pp. 912–918, 2004.
[97]
W. J. Brown, D. McLaughlin, J. Leung et al., “Physical activity and all-cause mortality in older women and men,” British Journal of Sports Medicine, vol. 46, pp. 664–668, 2012.
[98]
C. A. DeSouza, L. F. Shapiro, C. M. Clevenger et al., “Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men,” Circulation, vol. 102, no. 12, pp. 1351–1357, 2000.
[99]
S. Taddei, F. Galetta, A. Virdis et al., “Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes,” Circulation, vol. 101, no. 25, pp. 2896–2901, 2000.
[100]
T. Lauer, C. Heiss, J. Balzer et al., “Age-dependent endothelial dysfunction is associated with failure to increase plasma nitrite in response to exercise,” Basic Research in Cardiology, vol. 103, no. 3, pp. 291–297, 2008.
[101]
F. Franzoni, F. Galetta, C. Morizzo et al., “Effects of age and physical fitness on microcirculatory function,” Clinical Science, vol. 106, no. 3, pp. 329–335, 2004.
[102]
J. Karolkiewicz, L. Szczêsniak, E. Deskur-Smielecka, A. Nowak, R. Stemplewski, and R. Szeklicki, “Oxidative stress and antioxidant defense system in healthy, elderly men: relationship to physical activity,” Aging Male, vol. 6, no. 2, pp. 100–105, 2003.
[103]
X. Cheng, R. C. M. Siow, and G. E. Mann, “Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway,” Antioxidants and Redox Signaling, vol. 14, no. 3, pp. 469–487, 2011.
[104]
W. Bao, F. Song, X. Li et al., “Plasma heme oxygenase-1 concentration is elevated in individuals with type 2 diabetes mellitus,” PLoS One, vol. 5, no. 8, Article ID e12371, 2010.
[105]
E. Babusikova, M. Jesenak, P. Durdik, D. Dobrota, and P. Banovcin, “Exhaled carbon monoxide as a new marker of respiratory diseases in children,” Journal of Physiology and Pharmacology, vol. 59, supplement 6, pp. 9–17, 2008.
[106]
G. F. Vile and R. M. Tyrrell, “Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin,” Journal of Biological Chemistry, vol. 268, no. 20, pp. 14678–14681, 1993.
[107]
S. Bélanger, J.-C. Lavoie, and P. Chessex, “Influence of bilirubin on the antioxidant capacity of plasma in newborn infants,” Biology of the Neonate, vol. 71, no. 4, pp. 233–238, 1997.
[108]
S. W. Ryter, J. Alam, and A. M. K. Choi, “Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications,” Physiological Reviews, vol. 86, no. 2, pp. 583–650, 2006.
[109]
A. M. Niess, F. Passek, I. Lorenz et al., “Expression of the antioxidant stress protein heme oxygenase-1 (HO-1) in human leukocytes: acute and adaptational responses to endurance exercise,” Free Radical Biology and Medicine, vol. 26, no. 1-2, pp. 184–192, 1999.
[110]
M. Asghar, L. George, and M. F. Lokhandwala, “Exercise decreases oxidative stress and inflammation and restores renal dopamine D1 receptor function in old rats,” American Journal of Physiology—Renal Physiology, vol. 293, no. 3, pp. F914–F919, 2007.
[111]
I. Fleming and R. Busse, “Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 284, no. 1, pp. R1–R12, 2003.
[112]
T. Fukai, M. R. Siegfried, M. Ushio-Fukai, Y. Cheng, G. Kojda, and D. G. Harrison, “Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training,” Journal of Clinical Investigation, vol. 105, no. 11, pp. 631–1639, 2000.
[113]
G. Kojda, Y. C. Cheng, J. Burchfield, and D. G. Harrison, “Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene,” Circulation, vol. 103, no. 23, pp. 2839–2844, 2001.
[114]
R. Hambrecht, V. Adams, S. Erbs et al., “Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase,” Circulation, vol. 107, no. 25, pp. 3152–3158, 2003.
[115]
R. Hambrecht, A. Wolf, S. Gielen et al., “Effect of exercise on coronary endothelial function in patients with coronary artery disease,” The New England Journal of Medicine, vol. 342, no. 7, pp. 454–460, 2000.
[116]
R. Hambrecht, S. Gielen, A. Linke et al., “Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: a randomized trial,” Journal of the American Medical Association, vol. 283, no. 23, pp. 3095–3101, 2000.
[117]
B. D. Johnson, K. J. Mather, and J. P. Wallace, “Mechanotransduction of shear in the endothelium: basic studies and clinical implications,” Vascular Medicine, vol. 16, pp. 365–377, 2011.
[118]
F. R. M. Laurindo, M. D. A. Pedro, H. V. Barbeiro et al., “Vascular free radical release: ex vivo and in vivo evidence for a flow- dependent endothelial mechanism,” Circulation Research, vol. 74, no. 4, pp. 700–709, 1994.
[119]
G. W. de Keulenaer, D. C. Chappell, N. Ishizaka, R. M. Nerem, R. W. Alexander, and K. K. Griendling, “Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase,” Circulation Research, vol. 82, no. 10, pp. 1094–1101, 1998.
[120]
G. R. Drummond, H. Cai, M. E. Davis, S. Ramasamy, and D. G. Harrison, “Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide,” Circulation Research, vol. 86, no. 3, pp. 347–354, 2000.
[121]
H. Cai, M. E. Davis, G. R. Drummond, and D. G. Harrison, “Induction of endothelial NO synthase by hydrogen peroxide via a Ca2+/calmodulin-dependent protein kinase II/janus kinase 2-dependent pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 10, pp. 1571–1576, 2001.
[122]
J. W. E. Rush, J. R. Turk, and M. H. Laughlin, “Exercise training regulates SOD-1 and oxidative stress in porcine aortic endothelium,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 284, no. 4, pp. H1378–H1387, 2003.
[123]
S. Maeda, J. Sugawara, M. Yoshizawa et al., “Involvement of endothelin-1 in habitual exercise-induced increase in arterial compliance,” Acta Physiologica, vol. 196, no. 2, pp. 223–229, 2009.
[124]
C. Kasapis and P. D. Thompson, “The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review,” Journal of the American College of Cardiology, vol. 45, no. 10, pp. 1563–1569, 2005.
[125]
E. P. Plaisance and P. W. Grandjean, “Physical activity and high-sensitivity C-reactive protein,” Sports Medicine, vol. 36, no. 5, pp. 443–458, 2006.
[126]
K. E. Fallon, S. K. Fallon, and T. Boston, “The acute phase response and exercise: court and field sports,” British Journal of Sports Medicine, vol. 35, no. 3, pp. 170–173, 2001.
[127]
D. C. Nieman, J. M. Davis, D. A. Henson et al., “Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine levels after a 3-h run,” Journal of Applied Physiology, vol. 94, no. 5, pp. 1917–1925, 2003.
[128]
C. Keller, A. Steensberg, H. Pilegaard et al., “Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content,” The FASEB Journal, vol. 15, no. 14, pp. 2748–2750, 2001.
[129]
M. A. Febbraio and B. K. Pedersen, “Contraction-induced myokine production and release: is skeletal muscle an endocrine organ?” Exercise and Sport Sciences Reviews, vol. 33, no. 3, pp. 114–119, 2005.
[130]
A. R. Nielsen, R. Mounier, P. Plomgaard et al., “Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition,” Journal of Physiology, vol. 584, no. 1, pp. 305–312, 2007.
[131]
B. K. Pedersen and M. A. Febbraio, “Point: interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis,” Journal of Applied Physiology, vol. 102, no. 2, pp. 814–819, 2007.
[132]
B. K. Pedersen and H. Bruunsgaard, “Possible beneficial role of exercise in modulating low-grade inflammation in the elderly,” Scandinavian Journal of Medicine and Science in Sports, vol. 13, no. 1, pp. 56–62, 2003.
[133]
A. Festa, R. D'Agostino Jr., G. Howard, L. Mykk？nen, R. P. Tracy, and S. M. Haffner, “Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS),” Circulation, vol. 102, no. 1, pp. 42–47, 2000.
[134]
R. Starkie, S. R. Ostrowski, S. Jauffred, M. Febbraio, and B. K. Pedersen, “Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans,” The FASEB Journal, vol. 17, no. 8, pp. 884–886, 2003.
[135]
C. Keller, P. Keller, M. Giralt, J. Hidalgo, and B. K. Pedersen, “Exercise normalises overexpression of TNF-α in knockout mice,” Biochemical and Biophysical Research Communications, vol. 321, no. 1, pp. 179–182, 2004.
[136]
T. van der Poll, S. M. Coyle, K. Barbosa, C. C. Braxton, and S. F. Lowry, “Epinephrine inhibits tumor necrosis factor-α and potentiates interleukin 10 production during human endotoxemia,” Journal of Clinical Investigation, vol. 97, no. 3, pp. 713–719, 1996.
[137]
E. W. Petersen, A. L. Carey, M. Sacchetti et al., “Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro,” American Journal of Physiology—Endocrinology and Metabolism, vol. 288, no. 1, pp. E155–E162, 2005.
[138]
V. Wallenius, K. Wallenius, B. Ahrén et al., “Interleukin-6-deficient mice develop mature-onset obesity,” Nature Medicine, vol. 8, no. 1, pp. 75–79, 2002.
[139]
G. van Hall, A. Steensberg, M. Sacchetti et al., “Interleukin-6 stimulates lipolysis and fat oxidation in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 7, pp. 3005–3010, 2003.
[140]
C. Brandt and B. K. Pedersen, “The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 520258, 6 pages, 2010.
[141]
E. Hopps, B. Canino, and G. Caimi, “Effects of exercise on inflammation markers in type 2 diabetic subjects,” Acta Diabetologica, vol. 48, no. 3, pp. 183–189, 2011.
[142]
L. S. Quinn, B. G. Anderson, R. H. Drivdahl, B. Alvarez, and J. M. Argilés, “Overexpression of interleukin-15 induces skeletal muscle hypertrophy in vitro: implications for treatment of muscle wasting disorders,” Experimental Cell Research, vol. 280, no. 1, pp. 55–63, 2002.
[143]
M. Figueras, S. Busquets, N. Carbó et al., “Interleukin-15 is able to suppress the increased DNA fragmentation associated with muscle wasting in tumour-bearing rats,” FEBS Letters, vol. 569, no. 1–3, pp. 201–206, 2004.
[144]
E. Marzetti, L. Groban, S. E. Wohlgemuth et al., “Effects of short-term GH supplementation and treadmill exercise training on physical performance and skeletal muscle apoptosis in old rats,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 294, no. 2, pp. R558–R567, 2008.
[145]
E. Marzetti, J. M. Lawler, A. Hiona, T. Manini, A. Y. Seo, and C. Leeuwenburgh, “Modulation of age-induced apoptotic signaling and cellular remodeling by exercise and calorie restriction in skeletal muscle,” Free Radical Biology and Medicine, vol. 44, no. 2, pp. 160–168, 2008.
